The role of rare genetic variation and the innate immune system in the etiology of multiple sclerosis (MS) is being increasingly recognized. Recently, we described several rare variants in the NLRP1 gene, presumably conveying an increased risk for familial MS. In the present study we aimed to assess rare genetic variation in the inflammasome regulatory network. We performed whole exome sequencing of 319 probands, comprising patients with familial MS, sporadic MS and control subjects. 62 genes involved in the NLRP1/NLRP3 inflammasome regulation were screened for potentially pathogenic rare genetic variation. Aggregate mutational burden was analyzed, considering the variants’ predicted pathogenicity and frequency in the general population. We demonstrate an increased (p?=?0.00004) variant burden among MS patients which was most pronounced for the exceedingly rare variants with high predicted pathogenicity. These variants were found in inflammasome genes (NLRP1/3, CASP1), genes mediating inflammasome inactivation via auto and mitophagy (RIPK2, MEFV), and genes involved in response to infection with DNA viruses (POLR3A, DHX58, IFIH1) and to type-1 interferons (TYK2, PTPRC). In conclusion, we present new evidence supporting the importance of rare genetic variation in the inflammasome signaling pathway and its regulation via autophagy and interferon-ß to the etiology of MS.
The group of dystonia genes is expanding, and mutations of these genes have been associated with various combined dystonia syndromes. Among the latter, the cause of some dystonia parkinsonism cases remains unknown. To report patients with early-onset dystonia parkinsonism as a result of loss-of-function mutations in nuclear receptor subfamily 4 group A member 2. Phenotypic characterization and exome sequencing were carried out in 2 families. The 2 patients reported here both had a history of mild intellectual disability in childhood and subsequently developed dystonia parkinsonism in early adulthood. Brain magnetic resonance imaging was normal, and DATscan suggested bilateral dopaminergic denervation. Two frameshift mutations in NR4A2 were identified: a de novo insertion (NM_006186.3; c.326dupA) in the first case and another small insertion (NM_006186.3; c.881dupA) in the second. NR4A2 haploinsufficiency mutations have been recently reported in neurodevelopmental phenotypes. Our findings indicate that dystonia and/or parkinsonism may appear years after initial symptoms. Mutations in NR4A2 should be considered in patients with unexplained dystonia parkinsonism.
The pontocerebellar hypoplasias (PCH) represent a heterogeneous group of conditions characterized by structural abnormalities of central nervous system, typically involving cerebellum and ventral pons. In the present study, we propose a novel association between biallelic variants in ATOH1 and PCH with severe neurodevelopmental disorder. We report a family with two children affected with pontocerebellar dysplasia, severe motor and speech delay and sensorineural hearing loss. Using exome sequencing, we identified a homozygous rare missense variant in ATOH1 in both affected probands. ATOH1 encodes atonal bHLH transcription factor 1, a core neurogenic transcription factor that regulates cell differentiation in cerebellum, drives development of inner ear hair cells and is essential in development of neurosensory systems. Disruption of Atoh1 in mouse models was previously shown to result in severe cerebellar hypoplasia and hearing loss. The identified variant (NM_005172.1:c.481C)G, p.Arg161Gly) substitutes a highly conserved residue in the DNA binding domain of Atoh1. It is absent from control populations of the gnomAD project and our in-house database of 3000 exomes. We performed molecular modelling, which predicted that this change can affect DNA binding affinity of Atoh1 through distortion of its contacts to DNA and through remodelling of the helical part of HLH domain. In conclusion, we report a novel potential genetic cause of developmental brain anomalies, due to mutations in ATOH1. Although the evidence is currently too limited to conclusively establish its causality, this report may present basis for further studies on the role of ATOH1 in human disease.